Antiestrogens and SERMs (selective estrogen receptor modulators) such as tamoxifen and raloxifene are the most widely used agents in the treatment of hormone-responsive breast cancer and have proved to be very effective in breast cancer prevention. They are likely to play increasingly important roles in menopausal hormone replacement therapy as well. While it has long been known that the estrogen receptor (ER) is required for the actions of estrogens and SERMs, it is increasingly appreciated that the activity of the ER and the tissue selectivity of SERMs are markedly influenced by coregulator proteins. Also, the action of ER influences the expression pattern of a remarkable number of genes through a diversity of modes. In this project, we will combine modern technologies in an innovative two-pronged approach to understanding the molecular basis of SERM action: (a) a targeted investigation of the role of an ER-specific coregulator, REA (repressor of estrogen receptor activity), through the development of an REA knockout mouse, together with comparative studies on the influence of other corepressors in the action of SERMs, and (b) a global analysis of gene regulation by SERMs using microarrays, together with complementary bioinformatic, molecular, and biochemical analyses of regulated function. This research should provide a clearer understanding of the gene networks through which SERMs act, the cellular factors that determine SERM effectiveness and tissue selectivity, and the gene-regulating activities that contribute to their beneficial anti-proliferative and tumor suppressive actions in breast cancer treatment and prevention, and provide the optimal balance of tissue selective activities for hormone replacement therapy.